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Dual-target CAR-T Cell Therapy Targeting CD38 and BCMA for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)

First-generation Dual-target CAR-T Cell Therapy

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Our research team first developed a dual-target CAR-T cell therapy that simultaneously targets BCMA and CD38. This therapy has not only been successfully used to treat patients with relapsed/refractory multiple myeloma (RRMM) but has also demonstrated excellent efficacy and a favorable safety profile in clinical trials.

As shown in Figure A, we designed four CAR constructs: a BCMA CAR, a CD38 CAR, and two dual-target constructs: the 38BM CAR (with CD38 at the N-terminus) and the BM38 CAR (with BCMA at the N-terminus). The dual-target CAR constructs utilize an (EAAAK)₃ linker to connect two scFvs in tandem and contain a CD8 hinge region, a 4-1BB costimulatory domain, and a CD3ζ signaling domain. All CARs are membrane-targeted via a GM-CSF signal peptide and are constructed using a lentiviral expression system. Figure B shows that in primary T cells, the dual-target CAR expressed significantly more efficiently than single-target CARs (60.1% for the 38BM CAR and 59.4% for the BM38 CAR, compared to 48.2% for the BCMA CAR and 45.3% for the CD38 CAR, respectively). It also achieved excellent recognition of the CD38 antigen, demonstrating the stable expression and functional activity of the dual-target construct.

In a Phase I clinical trial, we enrolled 15 patients with severely relapsed/refractory multiple myeloma, all of whom received 38BM CAR-T cell infusions. Results showed an overall response rate (ORR) of 93.3% and a complete response rate (CR) of 66.7%, including patients who had previously failed multiple lines of therapy (e.g., proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies). Importantly, no severe cytokine release syndrome (≥Grade 3 CRS) occurred, demonstrating a superior safety profile compared to traditional CAR-T therapy.

In summary, our team has demonstrated for the first time the feasibility and advantages of a dual-targeting BCMA and CD38 synergistic mechanism in clinical practice, providing a solution to the antigen escape problem in multiple myeloma CAR-T cell therapy. This achievement not only demonstrates structural innovation but also lays a solid foundation for the development of next-generation multi-target immunotherapy products.

Dual-target CAR-T Cell Therapy Targeting CD38 and BCMA for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)

Second-generation Dual-target CAR-T Cell Therapy

Building on our team's successful development and clinical application of the world's first CD38 and BCMA dual-targeting CAR-T cell therapy, we have further developed a second-generation dual-targeting CAR-T product. While maintaining the original dual-targeting advantages, this therapy has undergone systematic upgrades in structural design, cell quality, functional regulation, and safety, aiming to enhance the durability, broad spectrum, and clinical adaptability of the treatment. This product has completed preclinical efficacy and safety evaluations, demonstrates clear advantages, and is currently applying for Phase I clinical trials.

The second-generation CAR structure features optimizations in the scFv sequence, flexible linker peptide, and transmembrane domain configuration, enhancing membrane expression stability and dual antigen recognition. The costimulatory signaling module utilizes a combination of 4-1BB and OX40 to enhance T cell expansion and survival, while the introduction of an artificial suicide switch (iCasp9) ensures risk management during treatment. During cell preparation, stem cell memory T cell subsets, such as Tscm/Tcm, are enriched, and low-dose IL-7/IL-15 stimulation is used to significantly enhance the in vivo persistence and functional activity of the CAR-T cells.

Preclinical validation in animal models has shown that this second-generation product demonstrates enhanced tumor clearance, prolonged tumor-free survival, and reduced inflammatory cytokine release in multiple myeloma xenograft models. Compared to the first-generation product, it offers significant advantages in addressing antigenic heterogeneity, delaying relapse, and reducing CRS.

This second-generation dual-target CAR-T therapy represents a key advancement from "highly effective response" to "long-term control." It is a global first and possesses clinically transformative potential. It is expected to usher in the next wave of multi-target CAR-T transformation in immunotherapy.

Dual-target CAR-T Cell Therapy Targeting CD38 and BCMA for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)

Third-generation Dual-target CAR-T Cell Therapy

Building on the foundations of the first two generations of CAR-T technology, our team has completed the structural design of the world's first third-generation dual-target (CD38 and BCMA) CAR-T cell therapy. This product represents a comprehensive upgrade in efficacy, sustainability, safety, and intelligent regulation capabilities. Integrating synthetic biology, logic gene circuits, and microenvironmental adaptation mechanisms, it represents a strategic advancement in dual-target CAR-T cell therapy from "precise identification" to "intelligent regulation" and industrial scalability. Currently, the product has completed all structural design and in vitro functional validation, and is preparing to initiate systematic preclinical trials.

The third-generation CAR structure utilizes a novel architecture: the recognition module retains the tandem dual scFvs for CD38 and BCMA, while optimizing the linker peptide and spatial conformation to achieve stable expression and coordinated recognition. In the signaling module, it introduces a triple signaling system (CD28/4-1BB/OX40) for the first time, significantly enhancing T cell activation potency, persistence, and resistance to exhaustion. The design also incorporates an iCasp9 suicide switch and a "dual antigen gating" logic element, activating the CAR signal only upon simultaneous recognition of CD38 and BCMA, significantly enhancing the controllability and safety margins of treatment.

To address the complex microenvironment of myeloma, the CAR-T cells are engineered to express CXCR3 and Heparanase, enhancing their ability to target and penetrate tumors. Furthermore, the T cells synthetically express exosomes with immune-remodeling functions (carrying miR-155 and low-dose IL-12), which synergistically modulate the tumor immune microenvironment and activate the endogenous immune system, thereby forming a dual-layered therapeutic mechanism of "cell-mediated tumorigenesis + microenvironmental regulation."

For manufacturing and evaluation, we have developed an AI-assisted structural optimization platform, combined with a high-throughput microfluidic screening system, to perform personalized antigen recognition simulations and drug efficacy predictions, laying a solid foundation for large-scale GMP-grade manufacturing and batch consistency verification. A core invention patent has been applied for for the overall design of this product, and we plan to complete all GLP-grade animal testing and pre-IND registration materials within the next year.

This third-generation dual-target CAR-T therapy not only achieves leapfrog innovation in structural design and functional mode, but also lays the technical foundation for future CAR-T products to move from "individualized experiments" to "modularization, controllability, and scale." It is expected to occupy a leading position in the international cell immunotherapy track.